Duration
The length of time an insulin continues to lower blood glucose. The four duration categoriesRxEd.org-Insulin Therapy are: Intro to duration Since activity decays on a half-life curve, there is no actual hard time when duration has ended -- it's a matter of degree. The usual time used for reference is either whatever the manufacturer claims, or the time when blood glucose levels have reached the same point they were at shot time. Any residual effect of the insulin beyond that time is carryover. Duration varies from species to species -- cats usually experience shorter durations than dogs on most insulins. Duration is also quite individual--can vary from patient to patient and even with the same patientBD Diabetes-Insulin for CatsInsulin Treatment-Individual Factors-PatientUpToDate. Though it is classed as a long-acting insulin, some humans, like their feline counterparts, do not get this type of duration from r-DNA ultralente insulin. For them, ultralente only has intermediate acting durationDiabetes Forecast-ADA, 2006-Page 2. The insulin time activity profilesHow Insulin Time Activity Profiles Are CreatedAbsorption Kinetics of Regular (Neutral) & Isophane (NPH) Insulin in the Normal Dog-Domestic Animal Endocrinology-1987Establishment of Time-Action Profiles for Regular (Neutral) NPH (Isophane) Insulin Using Pharmacodynamic Modeling-Diabetes Care-ADA-1994 you see are basically averages of blood glucose levels in a test group or groups of patients for a given time period. Some tested patients experienced longer than average duration, while for others it was less than average. Many of the duration test results done by manufacturers of human approved insulins are based on two patient groups--those with diabetes and non-diabetics who agreed to assist in the study. This combined and averaged data is used to generate the time activity profile. It means that there are VERY few with diabetes whose personal insulin activity profile is a perfect replica of those displayed. It follows then, that onset and peak times found on insulin time activity profiles are just as subject to variability as is duration, since they are all obtained in the manner above. Duration varies by species and strength, in addition to typeType I Diabetes and Insulin Therapy Nursing Clinics of North America-Hirsch-Farkas-Hirsch 1993. With regard to the non-analog insulins, duration can also be influenced by the size of the insulin dose itself, with larger doses having a stronger effect and a longer duration than smaller onesInsulin-Dependent Diabetes--Dr. Ragnar Hanas (Page 6). Duration Problems Short Duration This is a blood glucose graph of a cat who is receiving one shot of Bovine (beef) Lente insulin daily. After the 8 hour point, blood glucose values begin climbing. Interestingly enough, the insulin peak is within acceptable values. This insulin is working for this cat, but he/she is not getting enough duration from only one shot a day. Note: blood glucose values are shown in mmol/l (non-US) measurements. From what's seen here, it would appear that this is a problem which can be easily solved by increasing from once-daily to twice daily doses of the Bovine (beef) Lente. There appears not to be any Insulin resistance but just a matter of the Intermediate-acting beef Lente not providing adequate control when given only once a day. In contrast, let's look at a blood glucose graph of an animal who is being given Lente insulin twice daily, but has resistance to it. (Note: species of animal and insulin not stated. Blood glucose values shown in mmol/l (non-US) measurements.) You see the cat above with one injection of Bovine (beef) Lente respond to the insulin, but that it simply does not last long enough for him/her. Without knowledge of the species of animal, species of insulin or other information, it is not possible to even speculate as to why the twice daily Lente insulin is not working. There's negligible response to the two Lente insulin shots given in the graph of the animal shown below, and it's provided as an example of resistance/lack of duration only. Duration By Species With regard to cats and dogs, the closest or perfect amino acid matches to their own native insulin (cats=beef) (dogs=pork) means faster onset, peak and shorter duration, all other things held equal. For both, use of r-DNA/GE/GM insulins would mean a slower onset, peak and a longer durationDuration of GE Insulin in Pets-WSAVA 2001, due to these differences. It's just the reverse for people Duration of GE & Animal Insulins in Humans-Pharmacorama.comComparative of NPH (Isophane) Human & Porcine (Pork) Insulin in Diabetic Subjects-Diabetes Care-ADA-1982, with the r-DNA/GE/GM insulins acting and peaking faster and having less durationNew Patient & Transfer Studies-GE Duration Shorter Than Animal Insulins in Humans--Diabetes Care-ADA-1982 than either beefComparative Study of r-DNA NPH Insulin and Bovine NPH Insulin in Humans-Diabetes Care, 1982 or pork insulin products Comparison of Pork & GE Insulin in Human SubjectsHuman & Porcine NPH (Isophane) Insulins Unequally Effective in Diabetic Patients-Acta Diabetologica Latina-1984Diabetes-World Mailing List Web Site-Questions About InsulinChildrenWithDiabetes-Ask the Diabetes Team: People Have Faster Onset & Less Duration with GE Insulin than Either Beef or PorkDiabetes Health-GE Insulin of Shorter Duration Than Animal Insulin in Humans-Diabetes Health. Looking at the amino acid matches or differences, we can predict what they mean to duration. Dogs would have the shortest duration from pork insulin, slightly longer from r-DNA/GE/GM human insulin (one amino acid difference at insulin B chain, position #30)Veterinary Partner-The Hard to Regulate Diabetic Pet, but longer from beefEvaluation of an Insulin Zinc Suspension for Control of Naturally Occurring Diabetes Mellitus in Dogs-Australian Veterinary Journal,-2000 (Page 3)Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-OSU Endocrinology Symposium 2006-Nelson-Page 40, with amino acid differences in 2 positions--insulin A chain positions #8 & #10. In humans, their longest-duration insulin would be beefDiabetes-World Mailing List Web Site-Questions About InsulinSubcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factors-PubMed-Danish Medical Bulletin 1991RxEd.org-Insulin Therapy, due to the 3 amino acid differenceComparative Study of NPH (Isophane) Human Insulin & NPH (Isophane) Bovine Insulin in Human Subjects-Diabetes Care-ADA-1982. pork would have slightly more duration for them than r-DNA/GE/GM insulins, because of the 1 amino acid's differenceHuman & Porcine NPH (Isophane) Insulins are Unequally Effective in Diabetic Patients-Acta Diabetelogica-1984Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999Human, Porcine and Bovine Ultralente Insulin: Subcutaneous Administration in Normal Man-Diabetic Medicine-1986. One injection of Bovine Ultralente insulin can last up to 40 hours when administered to a human--longer than Lantus; it is also peaklessUse of Beef Ultralente for Basal Insulin Delivery-Diabetes Care-American Diabetes Association-1986Comparison of the Safety and Effectiveness of Human and Bovine Long-acting Insulins-Diabetes Research-1989Free Patents Online-Background of the Invention. Origin, species, or source is very important as it directly affects the absorption, peak and duration of an insulinDiabetes Forecast-ADA, 2006-Page 3 When looking at extending duration in this way, one needs to realize that the amino acid differences produce antibodies; these antibodies are what prevents the insulin from being used so quicklyVeterinary Partner-The Hard to Regulate Diabetic Pet. The possible drawback to extending duration by choosing insulins which are less akin to the native insulin of the diabetic is that the antibodies created by this may cause insulin resistanceWSAVA 2001-Diabetes Mellitus: Treatment Options-Dr. David Bruyette. Since the antibodies indicate an immune system reaction, all the effects of an overstimulated immune system should be considered. When there is sufficient resistance, duration can decrease instead of increase; at that point, the effectiveness of the insulin is compromisedSelecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-OSU Endocrinology Symposium 2006-Nelson-Page 40. Duration By Strength Comparing similar insulins with only strength differences means that the U100 strength insulin will have a slower onset, peak and longer duration than an insulin which is U40, U50 or even U80, which is available in some countriesThe Absorption of Subcutaneously Injected Short-Acting Soluble Insulin: Influence of Injection Technique & Concentration-Diabetes Care-ADA-1983, assuming the insulins are otherwise identicalAbsorption Comparison U40 & U100 Insulins-PubMedInsulin-Dependent Diabetes-Dr. Ragnar Hanas. An example of comparison for strength would be the 3 versions of 100% bovine PZI insulin available. Hypurin Bovine Protamine Zinc and Insuvet Protamine Zinc are both U100 insulins. BCP also produces a U100 version of its 100% beef PZI. All three would have the same length of duration. Switching strengths, however, changes things. Having BCP PZI in either U40 or U50 strength, as opposed to the BCP U100 PZI, Hypurin and Insuvet, means that the U40 and U50 strengths of the PZI BCP makes will have a faster onset, peak and less duration than the 3 U100 100% beef PZI insulins. The type of insulin is the same-PZI, the species is the same-beef. Duration By Dose The larger the dose of insulin, the longer it takes to be absorbedBernstein-The Law of Small Numbers Part 2 and the more duration it will haveDiabetic Phenomena-WSAVA 2008Absorption rates of subcutaneously injected insulin in the dog as calculated from the plasma insulin levels Diabetologia. 1983. Less strength=speed The hexamers of insulin tend to associate with each other (stay together) when coming in contact with zinc in the bloodstreamIslets of Hope-Insulin; they cannot be readily absorbed while they remain this way; this is also how endogenous insulin is stored in the bodies of those who don't have diabetes--in hexamer formWikipedia-Insulin. Diluting insulin into U40 strength forces them into dissociating (staying apart from each other, and becoming dimers and monomers), which means they are absorbedComparison of U100 and U40 Insulins-PubMedType 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999 better and more rapidly. An easy way to visualize this might be to think of a whole pie, slicing it into 6 pieces, then putting each piece on a separate plate. The pie can't be eaten until it's cut and everyone has a piece on his or her plate. While the body stores insulin in hexamer formWikipedia-Insulin, a normally working pancreas secretes insulin in monomer form, so there's no formation of hexamers by self-association and nothing to break down; the monomer insulin is ready to workChemistry and Pharmacology of Therapeutic Insulin Preparations, Abrams-Ogg, ACVIM 2007. The less strength an insulin has, the better it is absorbedInsulin Dependent Diabetes-Dr. Ragnar Hamas-1999 (Page 6)Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999Subcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factors--PubMed-Danish Medical Bulletin 1991. Better or faster absorption means a faster onset and peak but shorter duration. Using a less than U100 strength insulin is on the same principle as rapid-acting analog insulins. The analog insulins have their amino acid sequences altered to produce a faster onset and peak with shorter durationComparison of U40 & U100 Regular (Neutral) Insulin & Rapid-Acting Insulin Lispro (Humalog)-1998-PubMed. Diluting insulin from U100 strength does the same thing without altering the molecule. More strength=duration It is also possible to delay the absorption (thus increase the duration) of an insulin by increasing its strength. U500 insulinResource Guide-2005-American Diabetes Association, which is five times more concentrated than U100Humulin R 500, has been available through both Lilly and Novo Nordisk (Note: Their similar product is U400 strength insulinUse of U500 Insulin in Patients With Extreme Insulin Resistance-Diabetes Care-ADA-2005) by special order for many yearsDiabetes Forecast-ADA,2006-Page 4. The insulin's main use is for people with extreme insulin resistance, and is commercially available only in R/Neutral type. Though it is R/Neutral-type insulin, U400 & U500 insulinsDiabetes Monitor September 2008 have a pharmacokinetic profile more like NPH insulin than U100 R/NeutralDiabetes World Mailing List Web Site-Questions About InsulinU-500 Insulin-Diabetes Spectrum,March 20, 2009. Since there are no additives such as suspensions to alter R/Neutral insulin's action, the strength of the insulin formula hinders its breakdown into dimers and monomers, thus making it much slower-absorbed than U100 and lesser strength insulinsFive Fold Increase of Insulin Concentration Delays the Absorption of Human Insulin Injections in Pigs-Diabetes Research & Clinical Practice-2000Use of U500 R Insulin by Continuous Insulin Infusion (Insulin Pump)in Patients With Type 2 Diabetes & Severe Insulin Resistance Endocrine Practice-2006Humulin R-U500 Patient Leaflet. In cases of severe insulin resistance, using a much higher concentration of insulin appears to "negate" the effects of immune-related insulin resistance. The studies at the link below shows that there was no difference regarding antibodies when these patients were transferred from Iletin II NPH at U100 strength to a form of Iletin II R at U500 strength. However, the stronger insulin reduced their insulin needs from 33-75%U500 Insulin in the Treatment of Antibody-Mediated Insulin Resistance-Annals of Internal Medicine-1981Enhanced Efficacy of U500 Insulin in the Treatment of Insulin Resistance Caused by Target Tissue Insensitivity-American Journal of Medicine-1984. Whether the insulin is slowed by the size of its crystals, by its suspension, by the strength of its concentration, or has been designed to release slowly--all of these are different mechanisms with the same goal in mind--to keep the insulin in hexamer form (thus preventing its fast absorption) as long as possible. If you're having a hard time visualizing the role of strength regarding duration in an insulin, perhaps thinking of the following might help. If you had two stones, one which was pebble sized and the other which was somewhat larger, think about what it would take to break them down into small pieces with a hammer. It would take many more hammer blows to break the larger stone (U100 strength) into small pieces than for the pebble (U40 or U 50 strength); the duration of your work to shatter the larger one would be longer than for the smaller of the two. More Information *Variability of Insulin Action-Does it Matter-Insulin Journal 2008 References See also absorption, peak, onset, carryover and Insulin. Category:Terms Category:Action_profile Category:Tips Category:Treatments Category:Insulins Category:Regulation Category:Content Category:Insulin Terms